The melanocortin 1 receptor (MC1R) belongs to the family of melanocortin receptors (subfamily of G-protein coupled receptors, or GPCRs) comprised of five members (MC1R-MC5R), each encoded by a different gene. These receptors vary widely in their expression and tissue distribution, with the MC3R and MC4R being neuronal receptors, the MC2R predominantly expressed by the adrenal gland, and the MC1R and MC5R expressed in the skin. Alpha-melanocyte stimulating hormone (alpha-MSH) is a common native agonist for MC1R, MC3R, MC4R, and MC5R.
MC1R is expressed on the cell surface of melanocytes, cells that reside in the upper layer of the skin. Melanocytes provide photoprotection by synthesizing the pigment melanin that reduces the penetration of UV radiation and scavenges reactive oxygen radicals. UV radiation is the main etiological factor for skin cancers, including melanoma. Malignant transformation of melanocytes results in melanoma, the deadliest form of skin cancer. Melanoma incidence rates in the United States have been increasing for at least 30 years. From 2005 to 2009, the incidence of melanoma in Caucasians increased at a rate of 2.8% annually. American Cancer Society Facts and Figures (2013).
MC1R agonists work to protect the skin in two ways, enhancing repair of DNA damage and stimulating production of melanin by melanocytes. Studies have previously shown that activation of MC1R by its native, non-selective peptide ligand alpha melanocortin stimulating hormone (α-MSH) increases melanin synthesis. Treatment (6h-8h) of human melanocytes with α-MSH up-regulates expression of the MC1R gene, thus enhancing response of melanocytes to melanocortins. Further studies have shown that α-MSH enhances repair of UV-induced DNA photoproducts, which is expected to reduce mutations and malignant transformation, and inhibits apoptosis, and hence increases survival of human melanocytes with undamaged DNA.
For compounds targeting the skin, selectivity for MC1R is of particular importance. MC5R, while also expressed in the skin, is expressed on the sebaceous glands; its activation leads to increased sebum production, which causes acne. Zhang, L., et al., Melanocortin-5 receptor and sebogenesis, Eur. J. Pharmacol. 660(1): 202-06 (2011). Equally important is selectivity for MC1R versus MC3R and MC4R; commercial development of the potent but non-selective synthetic α-MSH analog melanotan II (MT-II) for sunless tanning was restricted by its off-target effects that included sexual arousal and spontaneous erections lasting for 1-5 hours, nausea, grade II somnolence, fatigue, stretching, yawning, and loss of appetite caused by undesired activation of MC3R and MC4R, in addition to the desired activation of MC1R. Dorr, R. T., et al., Evaluation of melanotan II, a superpoleni cyclic melanotropic peptide in a pilot phase-1 clinical study, Life Sci. 58(20): 1777-84 (1996); King, S. H., et al., Melanocortin receptors, melanotropic peptides and penile erections, Curr. Top. Med. Chem. 7(11): 1098-1106 (2007); Pfaus, J. G., et al., Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist, Proc. Nat'l. Acad. Sci. USA 101(27): 10201-04 (2004); Yang, Y., et al., Molecular basis for the interaction of [Nle4, D-Phe7]melanocyte stimulating hormone with the human melanocortin-1 receptor, J. Biol. Chem. 272(37): 2300-10 (1997).
Given the invasiveness of melanoma tumors, the poor prognosis, and the lack of effective treatment options, a substantial need exists for the development of selective agonists of MC1R for protecting skin and treating melanoma and other skin disorders that benefit from agonism of MC1R.